DESCRIPTION: This is a Phase I SBIR request for development of an in vitro tissue culture system which will permit studies of drugs' capability to enhance production of fetal hemoglobin. The Investigator stated that increased fetal hemoglobin in cells of patients with beta-hemoglobinopathy ameliorates the clinical symptoms of the underlying disease. Several pharmacologic agents have been used to stimulate HbF synthesis during recent years. Treatment of patients with 5-azacytidine and hydroxyurea has resulted in higher fetal hemoglobin levels. Despite this, the clinical benefit has not been clearly established. Most agents which have been employed are either toxic or have been implicated in carcinogenesis. Therefore there is considerable interest in identifying less toxic agents which have potential to increase fetal hemoglobin. Thus far, only a handful of these agents have been tested, mainly due to the lack of an appropriate experimental system that allows a rapid and accurate determination of the effect on hematologic cells. The Investigator indicates he has recently developed a novel, two-phase liquid culture system for growing erythroid progenitors derived from the peripheral blood of normal individuals and patients with hemoglobinopathies. He states that this system has proved to recapitulate in vitro many of the hematologic effects of hydroxyurea in vivo, including the stimulation of fetal hemoglobin production. The purpose of the proposed research is to utilize this methodology for measuring total and fetal hemoglobin. He would employ the method for mass screening of agents to determine their fetal hemoglobin stimulating potential. The ultimate goal of these studies is to identify drugs with little toxicity which have a significant potential for stimulation of fetal hemoglobin. He intends to optimize the conditions of their culture system for stimulation of hemoglobin production and then screen various agents to determine their effects. Subsequently, he will use the methodology to study the modes of action of agents which appear successful in stimulating fetal hemoglobin production.